Aromatic or aryl ketones are commonly used both as chemical intermediates and for producing many useful products. Methods to produce these compounds generally involve condensation of a carboxylic acid derivative with an active aromatic compound. The Friedel-Crafts acylation reaction, which introduces an acyl group into an aromatic ring to produce an aryl ketone, is considered the most important method for the formation of aryl ketones and is widely used commercially. In its most common form, the reaction occurs between an acyl halide, generally an acyl chloride, and an aromatic substrate and is catalyzed by aluminum trichloride. The mechanism of the reaction is represented by the following: 
(March, J., xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, Third Edition, John Wiley and Sons, New York, 1985, 565-566).
Despite its widespread acceptance, this common method has a number of serious disadvantages, including the generation of significant amounts of toxic byproducts which must be disposed of as hazardous waste materials (Desmurs, J. R., et al., 1997, Tetrahedron Lett 38:8871-8873). The amount and toxicity of the waste materials produced are a result of the chemical composition of the acyl chloride substrate and the aluminum chloride catalyst, the requirement for a stoichiometric amount of catalyst and the necessity of using a chlorinated hydrocarbon solvent, carbon disulfide or nitrobenzene (Smyth, T. R. et al., 1997, Org Proc Res Dev 264). Moreover, the spent catalyst is not readily recoverable for reuse (Kawada, A. et al., 1993, J Chem Soc, Chem Commun 1157-1158).
In recent years, much chemical and environmental research has been directed to improving the Friedel-Crafts acylation reaction. For example, attempts have been made to utilize substrates other than acyl halides for Friedel-Crafts acylation reactions. The majority of those methods utilize the readily reactive acyl anhydrides, but it has been recognized that these starting materials require catalyst in even greater amounts than do acyl halides. The additional catalyst is required due to the necessity for converting the acyl compound to the acyl cation (March, J., xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, Third Edition, John Wiley and Sons, New York, 1985, 565-566, 565). Moreover, such reactions only utilize a single acyl group, wasting the second acyl group.
A few studies have examined the direct use of carboxylic acid substrates. Unfortunately, these methods generally require the use of very strong or protic acids, such as hydrogen fluoride, sulfuric acid or polyphosphoric acid, as the catalyst (Lindley, D., et al., 1990, U.S. Pat. No. 4,894,482; Curtis, T. A. et al., U.S. Pat. No. 4,990,681; Sumner Jr., 1991,U.S. Pat. No. 5,041,616). Thus, the methods not only produce very toxic byproducts, they must be conducted in a highly corrosion-resistant environment.
The use of alternative catalysts has also been considered. For example, metal triflate salts have been used for organic synthesis reactions in general (Labrouillerer, M. et al., 1999, Tetrahedron Lett 40:285-286), and Friedel-Crafts acylations in particular (Kawada, A. et al., 1993, J Chem Soc, Chem Commun 1157-1158; J Chem Soc; Kawada, A. et al., 1994,Synlett 7:545-546;Desmurs, J. R., et al., 1997, Tetrahedron Lett 38:8871-8873). These studies utilized either acyl halides or anhydrides as substrates; therefore, the deficiencies associated with the use of those starting materials must be considered when evaluating these methods.
Thus, there exists a need for a more efficient and cost-effective method for producing aryl ketones that minimizes the generation of toxic byproducts.
The present invention is based, at least in part, on the discovery of an efficient, cost-effective method useful for the production of aryl ketones that minimizes the generation of toxic byproducts. The method utilizes a carboxylic acid substrate which eliminates both the necessity for forming the acyl chloride starting material, and the reaction step in which the acid chloride intermediate is formed in the common Friedel-Crafts acylation reaction. The method also utilizes a metal triflate salt catalyst which can be recovered and reused after the reaction is complete. In addition, water, the major byproduct formed by the reaction, is collected and removed during processing.
In one embodiment, a method of preparing an aryl ketone represented by the following structural formula: 
comprising heating an aromatic compound represented by the following structural formula: 
with a carboxylic acid in the presence of (1) a volatile organic compound which forms an azeotrope with water, and (2) a catalytic amount of a metal triflate salt, wherein the water of reaction is removed from the reaction mixture, and wherein:
R1 is the residue of the carboxylic acid;
R2 is an a hydrogen, hydroxy, alkyl, alkoxy, aryl, aryloxy or halogen group;
R3 is a hydrogen, hydroxy, alkyl, alkoxy, aryl, aryloxy or halogen group or any combination thereof; or
R2 and R3 collectively are a divalent chain of atoms forming a fused ring with the benzene ring to which each is attached.
In a preferred embodiment, the method is carried out at a temperature of less than about 85, 110, 132 or 140xc2x0 C.
In a preferred embodiment, the volatile organic compound is an aliphatic or aromatic hydrocarbon. In a preferred embodiment, the volatile organic compound is an aryl halide. In particularly preferred embodiments, the volatile organic compound is toluene.
In a preferred embodiment, the metal triflate catalyst is a rare metal triflate catalyst. In a particularly preferred embodiment, the metal triflate catalyst is a rare earth metal triflate catalyst.
In another embodiment, an improved Friedel-Crafts acylation reaction is provided comprising the steps of generating an acylium ion through the acceptance of an electron pair from a carboxylic acid by a metal triflate catalyst, followed by loss of water in an organic solvent which forms an azeotrope with water; reacting the acylium ion with an aromatic substrate; and removing the water of reaction from the reaction mixture, thereby forming an aryl ketone.
In a preferred embodiment, the reaction is carried out at a temperature of less than about 85, 110, 132 or 140xc2x0 C.
In a preferred embodiment, the volatile organic solvent is an aliphatic or aromatic hydrocarbon. In a preferred embodiment, the volatile organic compound is an aryl halide. In a particularly preferred embodiment, the volatile organic solvent is toluene.
In a preferred embodiment, the metal triflate catalyst is a rare metal triflate catalyst. In a particularly preferred embodiment, the metal triflate catalyst is a rare earth metal triflate catalyst.
In another embodiment, a method of preparing an aryl ketone represented by the following structural formula: 
comprising heating an aromatic compound represented by the following structural formula at a temperature less than about 140xc2x0 C. 
xe2x80x83with a carboxylic acid in the presence of (1) toluene, and (2) a catalytic amount of a rare earth metal triflate, wherein the water of reaction is removed from the reaction mixture, and wherein:
R1 is the residue of the carboxylic acid;
R2 is a hydrogen, hydroxy, alkyl alkoxy, aryl, aryloxy or halogen group;
R3 is a hydrogen, hydroxy, alkyl, alkoxy, aryl, aryloxy, halogen group or any combination thereof; or
R2 and R3 collectively are a divalent chain of atoms forming a fused ring with the benzene ring to which each is attached.
A description of preferred embodiments of the invention follows. It will be understood that the particular embodiments are shown by way of illustration and not as limitations. The principle features of this invention can be employed in various embodiments without departing from the scope of the invention. All parts and percentages are by weight unless otherwise specified.
A variety of metal triflates can be used as catalysts in the methods of the invention. The language xe2x80x9cmetal triflatexe2x80x9d is intended to include a compound formed from a metal and a trifluoromethanesulfonate. Preferred compounds are salts. The salts can be either anhydrous salts or can contain waters of hydration.
A triflate catalyst can be formed from many metals. Any metal, which when combined with a trifluoromethanesulfonate to form a metal triflate, effectively catalyzes the reactions of the invention can be used. Preferred metal triflates include those in which the metal is a rare metal. The language xe2x80x9crare metalxe2x80x9d is intended to include a chemical element of Groups III, IV and V of the periodic table including the transition elements in the lanthanide and actinide series. Preferred rare metal triflates include the rare earth metals as well as indium triflate, hafnium triflate, bismuth triflate and thorium triflate. The language rare metal is intended to encompass the language xe2x80x9crare earth metalxe2x80x9d in its art recognized broadest form. Thus, the language rare earth metal is intended to include a chemical element from the group of chemically related elements of Group IIIB of the periodic table, e.g., the lanthanoid series, e.g., the lanthanide series plus the elements scandium and yttrium (Lewis, R., editor, xe2x80x9cHawley""s Condensed Chemical Dictionaryxe2x80x9d, Twelfth Edition, Von Nostrand Reinhold Company, New York, 1993, 992). Preferred rare earth metal triflate catalysts are those of the lanthanide series. Particularly preferred rare earth metal triflate catalysts include several from the lanthanide series including lanthanum triflate, cerium triflate, praseodymium triflate, neodymium triflate, samarium triflate, dysprosium triflate and ytterbium triflate, as well as scandium triflate and yttrium triflate.
The metal triflate catalysts can be obtained commercially, for example, indium triflate and ytterbium triflate can be purchased from the Strem Chemical Company, Newburyport, Massachusetts. Such catalysts are suitable for direct use in the anyhydrous form supplied.
Alternatively, the catalysts can be prepared from various starting materials. For example, the appropriate metal oxide can be slurried in water, mixed with a stoichiometric amount of trifluoromethanesulfonic acid and refluxed for a suitable period of time. The resulting suspension can then be filtered and dried to obtain the metal triflate.
A metal acetate or nitrate can also be used as a starting material for preparing a metal triflate. These starting materials can be dissolved in water. In some cases, heating is required to fully dissolve the materials. A stoichiometric amount of sodium hydroxide can be added to the solution. The precipitate formed upon the addition of the sodium hydroxide can be filtered and washed with water. This product is the metal hydroxide which can be mixed with trifluoromethanesulfonic acid to form the metal triflate catalyst.
Alternatively, metal triflates can also be prepared using a triphenyl compound as a starting material. For example, bismuth triflate can be prepared from triphenyl bismuth. Triphenyl bismuth can be slurried in methylene chloride, mixed with a stoichiometric amount of triflouromethanesulfonic acid and stirred for several minutes. The slurry can then be filtered and the product washed with methylene chloride.
In a typical method of the invention, a catalytic amount of a metal triflate is mixed with a carboxylic acid and an aromatic substrate in a volatile organic substrate.
The language xe2x80x9ca catalytic amountxe2x80x9d is intended to include the quantitative amount of catalyst required to produce a measurable amount of an aryl ketone from the starting materials contained in a reaction mixture.
The language xe2x80x9ccarboxylic acidxe2x80x9d is intended to include one of a wide variety of unsubstituted and substituted aliphatic, cycloaliphatic and aromatic carboxylic acids containing C1-C20 carbons. Carboxylic acids are represented by the following structural formula: 
wherein R1 is an unsubstituted or substituted alkyl from C1-C8 carbons, cyclohexyl, phenyl or substituted phenyl. Preferably, R1 is alkyl from C1-C10 carbons, phenyl or substituted phenyl.
The language xe2x80x9calkylxe2x80x9d is intended to include a straight chained or branched C1-C110 hydrocarbon. The language xe2x80x9clower alkylxe2x80x9d is intended to include a straight chained or branched C1-C6 hydrocarbon or a C3-C6 cyclic hydrocarbon which is completely saturated.
The language xe2x80x9caromaticxe2x80x9d is intended to include an activated carbocyclic ring system, e.g., an benzyl and fused polycyclic, carbocyclic ring system, e.g., naphthyl, anthracenyl and 1,2,3,4-tetrahydronaphthyl. In addition, aromatic groups include heteroaryl ring systems, e.g., thiophene, furan, pyrroles, and pyrans, and heteroaryl ring systems in which a carbocyclic aromatic ring, a carbocyclic non-aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings. For example, benzimidazole, thianaphthene, benzofuran and indole.
The volatile organic solvent can be an aliphatic or an aromatic hydrocarbon, e.g., toluene. The volatile organic solvent can also be an aryl halide. The language xe2x80x9caliphaticxe2x80x9d is intended to include a straight chained or branched C1-C18 hydrocarbon which is completely saturated or which contains one or more units of unsaturation, or a cyclic C3-C18 hydrocarbon which is completely saturated or which contains one or more unconjugated double bonds.
The reaction mixture is refluxed for an appropriate period of time. During the reflux period, the water produced as a byproduct of the reaction as a water-solvent azeotrope is removed from the reaction mixture using any method known to those of skill in the art of organic synthesis. A preferred method utilizes a Dean Stark trap.
The language xe2x80x9cazeotropexe2x80x9d is art recognized and intended to include a mixture which forms a constant boiling mixture with water at standard atmospheric pressure.
The resulting solution can then be allowed to cool. The metal triflate catalyst can be recovered from the reaction mixture by aqueous extraction. The organic layers can be washed with, for example, sodium bicarbonate to remove and recover unreacted carboxylic acid. The recovered solid is the aromatic ketone product represented by the following structural formula: 
wherein R
R1 is the residue of the carboxylic acid;
R2 is a hydrogen, hydroxy, alkyl, alkoxy, aryl, aryloxy or halogen group; and
R3 is a hydrogen, hydroxy, alkyl, alkoxy, aryl, aryloxy, halogen group or any combination thereof.
The language xe2x80x9chydroxyxe2x80x9d is intended to include an oxygen-hydrogen group, e.g.,- an OH group.
The language xe2x80x9calkoxyxe2x80x9d is intended to include an oxygen-alkyl group, e.g., an OCH3 group.
The language xe2x80x9carylxe2x80x9d is intended to include a carbocyclic aromatic ring system and a polycyclic, carbocyclic aromatic ring system.
The language xe2x80x9caryloxyxe2x80x9d is intended to include an oxygen-aryl group, e.g., an OpH.
The products formed by the methods of the invention can be analyzed using thin layer chromatography (TLC) using, for example, a 2:1 hexane:ethyl acetate mobile phase. Products can also be assessed using high pressure liquid chromatography (HPLC) using, for example, an Econosil(trademark)(Alltech Associates, Inc., Deerfield, Ill.) C18 column, a 70:30, methanol:H2O mobile phase, a flow rate of 1.0 ml/min, an ultraviolet wavelength of 254 nm. Nuclear magnetic resonance (NMR), alone or in combination with any of the other analysis systems can be used. In addition, product identity and product purity can be determined by measuring the melting point of the product and comparing it to published melting points.
As evidenced by the products described in the examples, the products formed by the methods of the invention contain an enhanced initial purity. Some products contain a higher initial purity than products formed by the methods of the prior art. Other products contain a lower percentage of contaminants, which are either difficult to remove from the product or whose removal generates toxic byproducts, than do products formed by prior art methods.
In another embodiment, the methods of the invention include an improved Friedel-Craft acylation reaction comprising the steps of generating an acylium ion through the acceptance of an electron pair from a carboxylic acid by a metal triflate catalyst, followed by loss of water in an organic solvent which forms an azeotrope with water; reacting the acylium ion with an aromatic substrate; and removing the water of reaction from the reaction mixture, thereby forming an aryl ketone.
The language xe2x80x9cacylium ionxe2x80x9d is intended to include the derivative of a substituted oxonium ion or its equivalent. Such ions are generally formed by reacting a substrate with a strong Lewis acid. The acylium ion is a strong electrophile and is represented by the following structural formula:
Rxe2x80x94Cxe2x89xa1O+
A typical reaction mechanism of the method is represented by the following: 
In the reaction depicted above, the highly reactive acylium ion or its equivalent is formed through the acceptance of an electron pair from a carboxylic acid by the metal triflate catalyst, represented by Mxe2x80x94(OTf)n, followed by loss of water in an organic solvent. The organic solvent utilized can be toluene or another solvent which forms an azeotrope with water. (In some reactions, the functions of the organic solvent and the aromatic substrate are performed by a single compound, for example, toluene can be used both as the solvent and the aromatic substrate.) The acylium ion is then reacted with an aromatic substrate. Water is collected and removed from the reaction mixture. An aryl ketone containing a group corresponding to the group contained on the carboxylic acid substrate is formed as a product of the reaction.
The methods of the invention provide numerous advantages which enhance the efficient and cost-effective production of aryl ketone products while minimizing the generation of hazardous byproducts. Several of these advantages flow from surprising and unexpected results achieved by the methods.
The methods generally require fewer process steps than the methods of the prior art. This is the result of the direct utilization of the carboxylic acid as the substrate rather than using the more reactive acyl chloride, since doing so obviates the necessity for forming the acyl chloride from the carboxylic acid. Use of the carboxylic acid also eliminates the reaction step in which the acid chloride intermediate is formed in the common Friedel-Crafts acylation reaction.
The methods are also quite flexible in several respects. They can be utilized with a broad range of metal triflate catalysts. This flexibility permits the cost of the catalyst which may fluctuate at different economic times, to be utilized as a factor in the selection of optimal materials and conditions. It is also readily possible to vary the simple reaction conditions, heating until reflux, if necessary to optimize performance of the reaction with any particular catalyst. It has also been discovered that the methods of the invention function quite well even when the metal triflate catalysts are not dry. This permits the use of metal triflate catalyst recovered from a previous reaction to be utilized without even being processed to a dry state. Recovered catalysts can even be added to new reaction mixtures while in solution (see Example 5).
The methods generate very few byproducts, and those generated are either of low toxicity or suitable for reuse, or both. In general, the byproducts produced are water, spent catalyst, residues from a wash to remove excess solvent, e.g., sodium bicarbonate, and distillates from the organic layer after it has been stripped to dryness. The water is removed during the reaction. The catalyst can be recovered for reuse. The residues of the wash are of low toxicity and thus, can be economically discarded or recycled. Similarly, the distillates from the organic layer are of generally low toxicity and, can, in addition, be recovered for reuse as the solvent in future reactions.
Moreover, it has been discovered that the products produced by the methods of the invention are of an enhanced purity. This description of enhanced purity does not mean that the products as initially produced by the methods of the invention necessarily contain a lower percentage of contaminants than similar products produced by methods of the prior art, although they may. Rather, it is intended to convey that the products generally contain fewer contaminants which are either difficult to remove or which generate toxic byproducts when removed.
The contents of all the patents, patent applications and other references cited are hereby expressly incorporated by reference in their entireties.